Cytosolic Peroxiredoxin Attenuates The Activation Of Jnk And P38 But Potentiates That Of Erk In Hela Cells Stimulated With Tumor Necrosis Factor-α

Sang Won Kang,Tong-Shin Chang,Tae-Hoon Lee,Eun Seon Kim,Dae-Yeul Yu,Sue Goo Rhee

doi:10.1074/jbc.m307698200

Abstract

Tumor necrosis factor-alpha (TNF-alpha) induces the activation of all three types of mitogen-activated protein kinase (MAPK): c-Jun NH(2)-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). This cytokine also induces the production of several types of reactive oxygen species, including H(2)O(2). With the use both of HeLa cells expressing wild-type or dominant negative forms of the cytosolic peroxidase peroxiredoxin II and of mouse embryonic fibroblasts deficient in this protein, we evaluated the roles of H(2)O(2) in the activation of MAPKs by TNF-alpha. In vitro kinase assays as well as immunoblot analysis with antibodies specific for activated MAPKs indicated that H(2)O(2) produced in response to TNF-alpha potentiates the activation of JNK and p38 induced by this cytokine but inhibits that of ERK. Our results also suggest that cytosolic peroxiredoxins are important regulators of TNF signaling pathways.

Highlights

Tumor necrosis factor-␣ (TNF-␣) induces the activation of all three types of mitogen-activated protein kinase (MAPK): c-Jun NH2-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). This cytokine induces the production of several types of reactive oxygen species, including H2O2. With the use both of HeLa cells expressing wild-type or dominant negative forms of the cytosolic peroxidase peroxiredoxin II and of mouse embryonic fibroblasts deficient in this protein, we evaluated the roles of H2O2 in the activation of MAPKs by TNF-␣
Our observations indicate that TNF-␣-induced activation of JNK and p38 is positively regulated by H2O2, whereas ERK activation in response to this cytokine is inhibited as a result of H2O2 production
TNF-␣ is an extracellular stimulus that induces the production in cells of O2., H2O2, and NO, all of which in turn are thought to participate in intracellular signaling pathways activated by this cytokine

Summary

Introduction

Tumor necrosis factor-␣ (TNF-␣) induces the activation of all three types of mitogen-activated protein kinase (MAPK): c-Jun NH2-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). This cytokine induces the production of several types of reactive oxygen species, including H2O2. MAPK kinase kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; ROS, reactive oxygen species; NAC, Nacetylcysteine; Trx, thioredoxin; PDGF, platelet-derived growth factor; Prx, peroxiredoxin; MEF, mouse embryonic fibroblast; DCFH-DA, 2Ј,7Јdichlorofluorescein diacetate; CM-H2DCFDA, 5(and 6)-chloromethyl2Ј,7Ј-dichlorofluorescein diacetate; GST, glutathione S-transferase; HA, hemagglutinin epitope; DMEM, Dulbecco’s modified Eagle’s medium; MBP, myelin basic protein. Opposite Effects of H2O2 on JNK or p38 versus ERK blasts in response to angiotensin II [18] or in smooth muscle cells in response to platelet-derived growth factor (PDGF) [19]

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